The present invention provides a dosing regimen for a selective S1P1 receptor agonist, by which adverse effects are minimized in subjects/patients during the initial treatment phase, or upon re-initiation of dosing after drug discontinuation.
Selective S1P1 receptor agonists are compounds which preferentially activate the human S1P1 receptor sub-type from among the S1P1, S1P2, S1P3, S1P4, and S1P5 family members of sphingosine-1-phosphate-sensitive human G-protein coupled receptors. S1P receptor agonists decrease the number of circulating lymphocytes in peripheral blood in humans or animals after e.g. oral administration, therefore they have therapeutic potential in a variety of diseases associated with a dysregulated immune system. For example, the non-selective S1P receptor agonist FTY720 has been found to reduce the rate of clinical relapses in multiple sclerosis patients (Kappos L et al., N Engl J Med. 2006 Sep. 14, 355(11): 1124-40).
However, S1P receptor agonists have been described to reduce heart rate in rodent animal models, an effect that has been attributed to the activation of the S1P3 receptor in the sinoatrial nodal tissue of the heart, which increases the IK,ACh inward rectifier current, and slows the sinoatrial pacemaker (Hale J J et al., Bioorg Med Chem Lett. 2004, 14(13): 3501-5; Bünemann Metal., J Physiol 1995, 489: 701-707; Guo J et al., Pflugers Arch 1999, 438: 642-648; Ochi R et al., Cardiovasc Res 2006, 70: 88-96). Moreover, the non-selective S1P receptor agonist FTY720 reduces heart rate in humans (Koyrakh L et al., Am J Transplant 2005, 5: 529-536), and the literature suggests that S1P1 selective compounds would have diminished effects on heart rate in humans, compared to non-selective S1P receptor agonists (Himmel H M et al., Mol Pharmacol 2000, 58: 449-454; Peters S L, Alewijnse A E, Curr Opin Pharmacol. 2007, 7(2): 186-92; Fujishiro J et al., Transplantation 2006, 82(6): 804-12; Sanna M G et al., J Biol Chem. 2004, 279(14): 13839-48).